A Pilot Trial to Assess Potential Effects of Selective Intracoronary Bone Marrow–Derived Progenitor Cell Infusion in Patients With Nonischemic Dilated CardiomyopathyCLINICAL PERSPECTIVE

Background— Intracoronary administration of bone marrow–derived progenitor cells (BMC) was shown to improve coronary microvascular function in ischemic heart disease. Because coronary microvascular dysfunction is implicated in the pathogenesis and prognosis of nonischemic dilated cardiomyopathy (DCM), we investigated the effects of intracoronary BMC administration in patients with DCM. Methods and Results— Intracoronary infusion of BMC was performed in 33 patients with DCM by using an over-the-wire balloon catheter. Left ventricular contractility at baseline and after 3 months was assessed by analysis of left ventricular angiograms. Coronary hemodynamics were determined by intracoronary Doppler wire measurements. After 3 months, regional wall motion of the target area (contractility from −1.08±0.39 to −0.97±0.47 SD/chord, P =0.029) and global left ventricular ejection fraction (from 30.2±10.9 to 33.4±11.5%, P <0.001) were improved. Increase of regional contractile function was directly related to the functionality of the infused cells as measured by their colony-forming capacity. Minimal vascular resistance index was significantly reduced in the BMC-treated vessel after 3 months (from 1.53±0.63 to 1.32±0.61 mm Hg · s/cm; P =0.002, n=24), whereas no changes were observed in the reference vessel (from 1.60±0.45 to 1.49±0.45 mm Hg · s/cm; P =0.133, n=13). Twelve months after BMC infusion, N-terminal prohormone brain natriuretic peptide (NT-proBNP) serum levels were decreased, suggesting a beneficial effect on left ventricular remodeling processes (from 1610±993 to 1473±1147 pg/mL; P =0.038 for logNT-proBNP, n=26). Conclusions— Intracoronary administration of BMC seems to be associated with improvements in cardiac contractile and microvascular function in patients with DCM. Thus, randomized blinded studies are warranted to evaluate potential clinical benefits of intracoronary BMC administration in patients with DCM. Received August 26, 2008; accepted June 24, 2009.

[1]  Filippo Crea,et al.  Coronary microvascular dysfunction. , 2013, The New England journal of medicine.

[2]  F. Kiessling,et al.  Sustained Persistence of Transplanted Proangiogenic Cells Contributes to Neovascularization and Cardiac Function After Ischemia , 2008, Circulation research.

[3]  J. Hare,et al.  Cardiac regeneration and stem cell therapy , 2008, Current opinion in organ transplantation.

[4]  Douglas Losordo,et al.  Endothelial progenitor cells in neovascularization of infarcted myocardium. , 2008, Journal of molecular and cellular cardiology.

[5]  W. Brenner,et al.  Pilot Trial on Determinants of Progenitor Cell Recruitment to the Infarcted Human Myocardium , 2008, Circulation.

[6]  Mark A Sussman,et al.  Bones of contention: marrow-derived cells in myocardial regeneration. , 2008, Journal of molecular and cellular cardiology.

[7]  L. Amado,et al.  Early improvement in cardiac tissue perfusion due to mesenchymal stem cells. , 2008, American journal of physiology. Heart and circulatory physiology.

[8]  Jeroen J. Bax,et al.  Intramyocardial injection of autologous bone marrow mononuclear cells in patients with chronic myocardial infarction and severe left ventricular dysfunction. , 2007, The American journal of cardiology.

[9]  Amit N. Patel,et al.  Stem cell therapy for the treatment of heart failure , 2007, Current opinion in cardiology.

[10]  K. Poh,et al.  Intramyocardial Transplantation of Autologous CD34+ Stem Cells for Intractable Angina: A Phase I/IIa Double-Blind, Randomized Controlled Trial , 2007, Circulation.

[11]  M. Al-mallah,et al.  Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. , 2007, Archives of internal medicine.

[12]  E. Seifried,et al.  Transcoronary Transplantation of Functionally Competent BMCs Is Associated With a Decrease in Natriuretic Peptide Serum Levels and Improved Survival of Patients With Chronic Postinfarction Heart Failure: Results of the TOPCARE-CHD Registry , 2007, Circulation research.

[13]  I. Komuro,et al.  p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload , 2007, Nature.

[14]  A. Zeiher,et al.  Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. , 2007, European heart journal.

[15]  I. Shiojima,et al.  Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. , 2006, Genes & development.

[16]  A. Zeiher,et al.  Transcoronary transplantation of progenitor cells after myocardial infarction. , 2006, The New England journal of medicine.

[17]  L. Stevenson Implantable cardioverter-defibrillators for primary prevention of sudden death in heart failure: are there enough bangs for the bucks? , 2006, Circulation.

[18]  Paul Dendale,et al.  Recovery of Regional but Not Global Contractile Function by the Direct Intramyocardial Autologous Bone Marrow Transplantation: Results From a Randomized Controlled Clinical Trial , 2006, Circulation.

[19]  Roberto Bolli,et al.  Life and Death of Cardiac Stem Cells: A Paradigm Shift in Cardiac Biology , 2006, Circulation.

[20]  F. Girolami,et al.  Relevance of coronary microvascular flow impairment to long-term remodeling and systolic dysfunction in hypertrophic cardiomyopathy. , 2006, Journal of the American College of Cardiology.

[21]  C. Heeschen,et al.  Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. , 2005, Journal of molecular and cellular cardiology.

[22]  F. Emmrich,et al.  Transplantation of Blood-Derived Progenitor Cells After Recanalization of Chronic Coronary Artery Occlusion: First Randomized and Placebo-Controlled Study , 2005, Circulation research.

[23]  Joshua M Hare,et al.  Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[24]  I. Shiojima,et al.  Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. , 2005, The Journal of clinical investigation.

[25]  Stefanie Dimmeler,et al.  Unchain my heart: the scientific foundations of cardiac repair. , 2005, The Journal of clinical investigation.

[26]  W. Vaughn,et al.  Mesenchymal Stem Cells Differentiate into an Endothelial Phenotype, Enhance Vascular Density, and Improve Heart Function in a Canine Chronic Ischemia Model , 2005, Circulation.

[27]  M. Burnett,et al.  Marrow-Derived Stromal Cells Express Genes Encoding a Broad Spectrum of Arteriogenic Cytokines and Promote In Vitro and In Vivo Arteriogenesis Through Paracrine Mechanisms , 2004, Circulation research.

[28]  J. Zell,et al.  Evaluation of myocardial blood flow reserve in patients with chronic congestive heart failure due to idiopathic dilated cardiomyopathy. , 2003, The American journal of cardiology.

[29]  A. Zeiher,et al.  Infarct Remodeling After Intracoronary Progenitor Cell Treatment in Patients With Acute Myocardial Infarction (TOPCARE-AMI): Mechanistic Insights From Serial Contrast-Enhanced Magnetic Resonance Imaging , 2003, Circulation.

[30]  James T. Willerson,et al.  Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure , 2003, Circulation.

[31]  A. Zeiher,et al.  Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) , 2002, Clinical research in cardiology : official journal of the German Cardiac Society.

[32]  D. Neglia,et al.  Prognostic Role of Myocardial Blood Flow Impairment in Idiopathic Left Ventricular Dysfunction , 2002, Circulation.

[33]  D. Neglia,et al.  Myocardial blood flow response to pacing tachycardia and to dipyridamole infusion in patients with dilated cardiomyopathy without overt heart failure. A quantitative assessment by positron emission tomography. , 1995, Circulation.

[34]  P. Ganz,et al.  Atherosclerosis impairs flow-mediated dilation of coronary arteries in humans. , 1989, Circulation.

[35]  W. Hofmann,et al.  Normalization of coronary blood flow in the infarct-related artery after intracoronary progenitor cell therapy: , 2006, Clinical Research in Cardiology.